Antibodies to Define Molecular Mechanisms of Hypertriglyceridemia

描述（由申请人提供）：本申请涉及挑战领域（06）：使能技术和特定挑战主题06-HL-102，即开发用于心血管和肺部疾病靶点分子成像的高亲和力/高特异性靶向分子探针。我们将使用抗体探针来更好地确定高胆固醇血症的发病机制。高胆固醇血症是由脂蛋白脂酶（LPL）的遗传缺陷引起的，但大多数高胆固醇血症病例的病因仍然是神秘的。幸运的是，最近关于LPL进入毛细血管的机制的发现可能会揭开这个谜团。通过应用脂解和分子成像的新发现，我们将更好地确定高脂血症的基础。LPL导致的脂解减少是许多高脂血症病例的基础，但对脂解缺陷的解释是神秘的。当人们考虑到许多高脂血症患者的组织和"肝素后"血浆中LPL水平正常这一事实时，这个谜团就复杂了。可以说，高脂血症的机制构成了脂蛋白代谢中最令人困惑的谜团。我们对这个问题有了新的见解。我们鉴定了一种内皮细胞蛋白GPIHBP1，其结合LPL并作为毛细血管中脂解的"平台"。此外，我们发现GPIHBP1作为"LPL转运体。"GPIHBP1将LPL从内皮细胞的基底外侧转运到顶端（管腔）表面，在那里它水解脂蛋白甘油三酯。我们推测许多高脂血症病例是由于GPIHBP1介导的LPL向毛细血管转运缺陷所致。Stephen Young、Loren Fong及其同事开发了针对GPIHBP1和LPL的单克隆和多克隆抗体，以及用于评估GPIHBP1和LPL功能的新基因靶向模型。同时，安娜吴博士和托芙奥拉夫森是免疫诊断和分子成像的先驱。总之，我们已经迈出了第一步，用124I标记的抗GPIHBP1单克隆抗体进行了基于正电子的分子成像研究。在接下来的两年里，我们将开发分子成像方法来测量GPIHBP1和LPL的毛细血管内水平。这个问题只能通过分子成像技术来解决。我们的成像研究将开始与小鼠模型，但我们将同时准备所需的试剂，在人体脂肪分解的分子分析。我们希望我们的努力将澄清高胆固醇血症的机制，并建立分子影像学作为一个重要的工具，在了解高胆固醇血症。H 公共卫生相关性：脂肪分解缺陷可导致动脉粥样硬化以及危及生命的动脉粥样硬化发作。遗传学研究表明，加速脂解速率导致血浆脂质水平降低和冠状动脉疾病患病率降低。通过分子成像确定毛细血管内GPIHBP1和LPL的水平，将大大提高对高脂血症分子基础的理解。

DESCRIPTION (provided by applicant): This application addresses Challenge Area (06): Enabling Technologies and Specific Challenge Topic 06- HL-102, which is to develop high affinity/high specificity targeted molecular probes for molecular imaging of cardiovascular and pulmonary disease targets. We will use antibody probes to better define the pathogenesis of hypertriglyceridemia. Hypertriglyceridemia is caused by inherited defects in lipoprotein lipase (LPL), but the etiology of most cases of hypertriglyceridemia remains mysterious. Fortunately, recent discoveries on the mechanism by which LPL enters capillaries may uncloak the mystery. By applying new discoveries in lipolysis and molecular imaging, we will better define the underpinnings of hypertriglyceridemia. Reduced lipolysis by LPL underlies many cases of hypertriglyceridemia, but the explanation for the defective lipolysis is mysterious. This mystery is compounded when one considers the fact that many patients with hypertriglyceridemia have normal levels of LPL both in tissues and in the "postheparin" plasma. Arguably, the mechanisms for hypertriglyceridemia constitute the most perplexing riddle in lipoprotein metabolism. We have fresh insights into this problem. We identified an endothelial cell protein, GPIHBP1, which binds LPL and serves as a "platform" for the lipolysis in capillaries. Also, we found that GPIHBP1 serves as the "LPL transporter." GPIHBP1 transports LPL from the basolateral to the apical (luminal) surface of endothelial cells, where it hydro-lyzes lipoprotein triglycerides. We hypothesize that many cases of hypertriglyceridemia are due to defective GPIHBP1-mediated transport of LPL into capillaries. Drs. Stephen Young, Loren Fong, and colleagues have developed monoclonal and polyclonal antibodies against GPIHBP1 and LPL, as well as new gene-targeted models for assessing GPIHBP1 and LPL function. Meanwhile, Drs. Anna Wu and Tove Olafsen are pioneers in immunodiagnostics and molecular imaging. Together, we have already taken the first step and performed positron-based molecular imaging studies with an 124I-labeled monoclonal antibody against GPIHBP1. Over the next two years, we will develop molecular imaging approaches to measure the intracapillary levels of both GPIHBP1 and LPL. This topic can only be approached with molecular imaging techniques. Our imaging studies will begin with mouse models, but we will simultaneously prepare the reagents required for molecular analysis of lipolysis in humans. We expect that our efforts will clarify the mechanisms of hypertriglyceridemia and establish molecular imaging as a critical tool in understanding hypertriglyceridemia. H PUBLIC HEALTH RELEVANCE: Defective lipolysis can lead to atherosclerosis as well as life-threatening episodes of atherosclerosis. Genetic studies have shown that accelerated rates of lipolysis lead to lower plasma lipid levels and a reduced prevalence of coronary disease. Molecular imaging to define intracapillary levels of GPIHBP1 and LPL will lead to a vastly improved understanding of the molecular underpinnings of hypertriglyceridemia.